John Marshall, MD: Tony, take us through the new medicines: regorafenib and TAS-102 (trifluridine/tipiracil). Talk about these drugs, and we’ll go through some of the trials and side effects. But, big picture, how are these therapies having an impact? What are the results of the trials?

Tanios Bekaii-Saab, MD: Once patients go through multiple lines of chemotherapy, plus/minus the biologics, we get to the point where we have 2 different options for those patients. They’re both oral single agents, regorafenib and TAS-102. TAS-102 is a more traditional cytotoxic agent, which belongs to that super family of fluoropyrimidines. It’s not 5-FU; it’s different. In fact, preclinically and clinically, it seems to work where 5-FU fails. Regorafenib, on the other hand, is a very dirty tyrosine kinase inhibitor—multiple, multiple targets; some of them we understand, others we may not understand as well—but works on the antiangiogenic agents and also has targets on the cancer cells. And both have been looked at in the refractory setting versus placebo, and they both have shown benefits versus placebo, but are not being compared head-to-head. We don’t have that comparison.

What we know is if they both seem to derive some benefit—and for few patients, there’s a lot of benefit, but for most, there’s little or no benefit as such—their toxicity profiles are different. Regorafenib has earlier toxicities, like hand and foot syndrome and fatigue. You see a bump in liver function, and they seem to actually adjust the toxicity while adjusting the dose. And patients may have a less rough ride after 2 to 3 weeks. TAS-102’s toxicities are mostly hematologic, although the other systemic toxicities seem to actually come up a little bit later for those patients who seem to benefit. So, different agents, different category of drugs. Both have their utility.

John Marshall, MD: Johanna, we know that these drugs don’t cause a lot of response. Frankly, second-line therapy doesn’t cause a lot of response, although some do, depending on the drugs and the approach. Patients seem to now be thinking about response and whether it’s online or they’re used to our talking about response. So, how do you discuss these drugs and their utility to a patient who’s wanting tumor shrinkage? What’s the language you’re using with patients in this space?

Johanna Bendell, MD: What I try to do is even when I first meet the patient, I tell them that stable disease can’t hurt them. If the tumor is not growing, it’s not going to hurt you. We’re trying to reinforce that with them. They get some practice on it from the first-line therapy because you get your biggest bang for your buck in your first couple set of restaging scans, and then things plateau out and it’s stable disease. And that’s the first time they start to learn that concept, that it’s okay as long as it’s not growing and they’re tolerating the therapy well. And so, when I talk to patients about both of these therapies, what we’re going to do is hopefully stop their disease from growing—not in everybody—but that will probably be the best outcome from these, that we do see occasional responses.

John Marshall, MD: So, it’s good. Did you use language around like how long you might be stable? Do you use some of the curves?

Johanna Bendell, MD: Gosh, that’s such a hard conversation to have because you can tell people things based on averages. But then it all depends on what their tumor is going to do to it. And so, people ask me a lot of times, “Is this better than getting nothing at all? I’ll say, “Well, we saw that people who got this lived longer.” “Well, how many months is it going to buy me?” And that’s a tricky question because we don’t actually know. We can tell what the average is, but you have to set them very, very clearly when you give them that data, that that might not be them either way.

John Marshall, MD: Alan, I never really expected this, but shifting from a regular visit to the infusion unit to now not going to the infusion unit is actually a loss for our patients. That was a touch point place for them, a safe haven, and now they’re not going there. And I’m feeling some of this back from my patients.

Alan P. Venook, MD: It’s a very important observation, where patients get great reassurance seeing the MD, seeing the infusion nurses. They know they’re being proactive. And we do find that patients, when they lose touch with us, many of them get despair. There’s a lot of depression that we see even though these patients are doing well. On the flip side, patients who are coming in frequently to the infusion center, they’ll see patients who aren’t doing so well and there may be some guilt associated with that. What we do is we’ve been very aggressive in intermixing psycho-oncology as well as symptom management in our practice, so patients can see those modalities at the same visit as they see us; go from one room to the next. And we find that’s incredibly valuable because patients will often not tell the doctor what they’ll tell the symptom management folks, and I think those are very important concepts. How patients cope and how they adjust, a lot of it is the environment that they’re in and how comfortable they are with their nurses, etc. So, it’s a very important point.

John Marshall, MD: Well, they’ve been going every 2 weeks for the last 2 years. They know the parking attendant. They like their Ativan (lorazepam) or their Decadron (dexamethasone) that day.

Alan P. Venook, MD: It’s stunning when patients will ask, “You mean I’m not coming back?” And to many of them, they may think this is the end of the road. The other thing that we work very hard at is keeping out in front of them the chance of research or other protocols. I must say I’ve never been one who would be the sunny side, the fantasy of you wait long enough and we’re going to find something for you. And yet, now I think genuinely we can do that. Because, really, the changes can be lightning-quick. We will tell patients, “Hold on. We really think the fields are changing at a pace where we may have something for you before long.”

John Marshall, MD: That feels less false.

Alan P. Venook, MD: I actually believe it now, and I used to not believe it. But if you look at the checkpoint inhibitors, they came from nowhere and just burst onto the scene. That’s a graphic example of a therapy that wasn’t on our radar. We’ve seen patients rise from the ashes with that treatment.

Transcript Edited for Clarity

Transcript:

John Marshall, MD: Tony, take us through the new medicines: regorafenib and TAS-102 (trifluridine/tipiracil). Talk about these drugs, and we’ll go through some of the trials and side effects. But, big picture, how are these therapies having an impact? What are the results of the trials?

Tanios Bekaii-Saab, MD: Once patients go through multiple lines of chemotherapy, plus/minus the biologics, we get to the point where we have 2 different options for those patients. They’re both oral single agents, regorafenib and TAS-102. TAS-102 is a more traditional cytotoxic agent, which belongs to that super family of fluoropyrimidines. It’s not 5-FU; it’s different. In fact, preclinically and clinically, it seems to work where 5-FU fails. Regorafenib, on the other hand, is a very dirty tyrosine kinase inhibitor—multiple, multiple targets; some of them we understand, others we may not understand as well—but works on the antiangiogenic agents and also has targets on the cancer cells. And both have been looked at in the refractory setting versus placebo, and they both have shown benefits versus placebo, but are not being compared head-to-head. We don’t have that comparison.

What we know is if they both seem to derive some benefit—and for few patients, there’s a lot of benefit, but for most, there’s little or no benefit as such—their toxicity profiles are different. Regorafenib has earlier toxicities, like hand and foot syndrome and fatigue. You see a bump in liver function, and they seem to actually adjust the toxicity while adjusting the dose. And patients may have a less rough ride after 2 to 3 weeks. TAS-102’s toxicities are mostly hematologic, although the other systemic toxicities seem to actually come up a little bit later for those patients who seem to benefit. So, different agents, different category of drugs. Both have their utility.

John Marshall, MD: Johanna, we know that these drugs don’t cause a lot of response. Frankly, second-line therapy doesn’t cause a lot of response, although some do, depending on the drugs and the approach. Patients seem to now be thinking about response and whether it’s online or they’re used to our talking about response. So, how do you discuss these drugs and their utility to a patient who’s wanting tumor shrinkage? What’s the language you’re using with patients in this space?

Johanna Bendell, MD: What I try to do is even when I first meet the patient, I tell them that stable disease can’t hurt them. If the tumor is not growing, it’s not going to hurt you. We’re trying to reinforce that with them. They get some practice on it from the first-line therapy because you get your biggest bang for your buck in your first couple set of restaging scans, and then things plateau out and it’s stable disease. And that’s the first time they start to learn that concept, that it’s okay as long as it’s not growing and they’re tolerating the therapy well. And so, when I talk to patients about both of these therapies, what we’re going to do is hopefully stop their disease from growing—not in everybody—but that will probably be the best outcome from these, that we do see occasional responses.

John Marshall, MD: So, it’s good. Did you use language around like how long you might be stable? Do you use some of the curves?

Johanna Bendell, MD: Gosh, that’s such a hard conversation to have because you can tell people things based on averages. But then it all depends on what their tumor is going to do to it. And so, people ask me a lot of times, “Is this better than getting nothing at all? I’ll say, “Well, we saw that people who got this lived longer.” “Well, how many months is it going to buy me?” And that’s a tricky question because we don’t actually know. We can tell what the average is, but you have to set them very, very clearly when you give them that data, that that might not be them either way.

John Marshall, MD: Alan, I never really expected this, but shifting from a regular visit to the infusion unit to now not going to the infusion unit is actually a loss for our patients. That was a touch point place for them, a safe haven, and now they’re not going there. And I’m feeling some of this back from my patients.

Alan P. Venook, MD: It’s a very important observation, where patients get great reassurance seeing the MD, seeing the infusion nurses. They know they’re being proactive. And we do find that patients, when they lose touch with us, many of them get despair. There’s a lot of depression that we see even though these patients are doing well. On the flip side, patients who are coming in frequently to the infusion center, they’ll see patients who aren’t doing so well and there may be some guilt associated with that. What we do is we’ve been very aggressive in intermixing psycho-oncology as well as symptom management in our practice, so patients can see those modalities at the same visit as they see us; go from one room to the next. And we find that’s incredibly valuable because patients will often not tell the doctor what they’ll tell the symptom management folks, and I think those are very important concepts. How patients cope and how they adjust, a lot of it is the environment that they’re in and how comfortable they are with their nurses, etc. So, it’s a very important point.

John Marshall, MD: Well, they’ve been going every 2 weeks for the last 2 years. They know the parking attendant. They like their Ativan (lorazepam) or their Decadron (dexamethasone) that day.

Alan P. Venook, MD: It’s stunning when patients will ask, “You mean I’m not coming back?” And to many of them, they may think this is the end of the road. The other thing that we work very hard at is keeping out in front of them the chance of research or other protocols. I must say I’ve never been one who would be the sunny side, the fantasy of you wait long enough and we’re going to find something for you. And yet, now I think genuinely we can do that. Because, really, the changes can be lightning-quick. We will tell patients, “Hold on. We really think the fields are changing at a pace where we may have something for you before long.”

John Marshall, MD: That feels less false.

Alan P. Venook, MD: I actually believe it now, and I used to not believe it. But if you look at the checkpoint inhibitors, they came from nowhere and just burst onto the scene. That’s a graphic example of a therapy that wasn’t on our radar. We’ve seen patients rise from the ashes with that treatment.